Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and liver cancer, and is the most common indication for liver transplantation in the United States. The hallmarks of the HCV infection are viral persistence and liver cell injury. The underlying molecular mechanisms remain poorly understood. Cytokines appear to play a critical role in viral clearance and liver tissue damage. The Long-Term Goal of our research program is to understand how antiviral cytokines modulate viral RNA replication and the predictive role of these cytokines in response to interferon alpha treatment. In support of this goal, our Preliminary Studies have 1) demonstrated that IFN` and FGF1 have a direct effect on HCV viral subgenomic RNA (replicon) replication in hepatoma cells; 2) identified several IFN` responsive genes potentially responsible for its antiviral activity in the replicon cell lines; 3) established a cytokine-related cDNA microarray system and established the feasibility of carrying out microarray experiment using liver biopsy tissues. These studies have led us to formulate a Central Hypothesis of this proposal, that antiviral cytokines such as IFN` or others are critical in viral clearance by direct inhibition of viral replication within hepatocytes; and the presence of these cytokines before IFN` treatment can predict the responsiveness to the therapy. In the Specific Aims we will: 1) determine the efficacy of cytokines such as IFN` and FGF1 on inhibiting HCV viral RNA replication and to identify the key intracellular signaling molecules responsible for this effect; and 2) identify cytokines that favor viral clearance versus viral persistence through analyzing HCV-infected liver tissues before and after IFN-based treatment. To address these aims, we will utilize the existing HCV replicon cell line for in vitro mechanistic studies and carry out microarray experiments using liver biopsy tissues to determine the role of antiviral cytokines in HCV-infected patients. This proposal will delineate how IFN` and FGF1 exert antiviral activity within hepatocytes, and will identify cytokines that predict viral clearance in HCV viral infection. This study will enhance our understanding of the host and hepatitis C virus interactions underlying the pathogenesis of viral chronic infection. The candidate's long-term career goal is to be an independent physician scientist conducting translational research. The immediate career goal is to develop the scientific reasoning and skills necessary for a successful research career by carrying out the current research proposal. Our institution provides an outstanding supportive environment for career development. This funding mechanism will give the candidate the opportunity to establish an independent research career.